(a) Field
The subject matter disclosed generally relates to methods for inhibiting cancer tumor growth in a patient. More specifically, the method relates to methods comprising administering to a patient a therapeutic monoclonal antibody specific for a tumor associated antigen in combination with at least one immunostimulatory compound, and at least one immune homeostatic checkpoint inhibitor.
(b) Related Prior Art
Quest PharmaTech has developed a series of monoclonal antibodies specific to tumor antigens such as CA125, MUC1, PSA, Her2/neu and other tumor associated antigens. Quest PharmaTech is developing these monoclonal antibody therapies as cancer immunotherapy specifically capable of stimulating anti-tumor immunity through altered antigen processing and presentation stimulated by these specific antibodies.
Demonstrations studies have been completed in animals and for several antibodies, namely AR20.5 and B43.13, in human clinical trials. Parallel to these efforts, immunologists studying the molecular events of adaptive immunity have defined the pathways of antigen recognition by specific T cells using T cell receptors that recognize peptide fragments of antigen in the context of MHC class I and II. The dynamics of an acute response require activation of second signals in addition to T cell receptor recognition to avoid induction of tolerance. The primary activating second signals are the interaction between B7.1 on antigen presenting cells (APC) and CD28 on the T cells. These second signals are induced in the pro-inflammatory microenvironment. Additional activating pathways have also been defined, as well as a redundant set of checkpoint pathways designed to limit antigen specific activation. These homeostatic checkpoint signals include the interaction of CTLA4 on T cells with B7.1 on APC and PD-1 on T cells with B7H1 on APC.
Interference with checkpoint inhibition results in prolongation and enhancement of specific immunity. This has been applied to the immunotherapy of multiple cancer types and as reported at the 2014 meeting of the American Society of Clinical Oncology, activation of immunity using molecules in development, as well as commercialized molecules in the case of one anti-CTLA-4 monoclonal antibody (ipilimumab), can result in predictable clinical responses, and durable control of tumor growth and, on occasion, shrinkage and elimination of disease in patients with advanced solid malignancy. Responses to therapy have been associated with the presence of mutations on common tumor antigens presumably creating Neoantigens that are more prone to immune attacks by endogenous T cells (Snyder et al ASCO Proceedings 2014 abstract 3003). The performance of immune checkpoint blockade therapies, however, remains limited, with responses seen in less than 50% of patents and complete responses observed in only a few percent of treated patients.
Therefore, there is a need for method that will improve the performance of immune checkpoint blockade therapies.